The present invention relates to certain purine derivatives. More particularly, the present invention relates to purin-2-ylcarboxamide derivatives, to their preparation, and to compositions, uses and intermediates used in the preparation thereof. These derivatives are selective, functional agonists of the human adenosine A2a receptor and may be used as anti-inflammatory agents in the treatment of, inter alia, diseases of the respiratory tract.
Adenosine is a ubiquitous molecule having a central role in mammalian intermediary metabolism. Independently, adenosine acts on multiple surface receptors to produce a variety of responses. Receptor classification has revealed the presence of at least four subtypes: A1, A2a, A2b and A3. Stimulation of adenosine A2 receptors on the surface of human neutrophils has been reported to potently inhibit a range of neutrophil functions. Activated neutrophils can damage lung tissue by release of reactive oxygen species, such as superoxide anion radicals (O2xe2x88x92), and granule products, such as human neutrophil elastase (HNE), amongst other inflammatory mediators. In addition, activated neutrophils perform both de novo synthesis and release of arachidonate products such as leukotriene B4 (LTB4). LTB4 is a potent chemo-attractant that recruits additional neutrophils to the inflammatory focus, whereas released O2xe2x88x92 and HNE adversely affect pulmonary extracellular matrix. The A2 receptor subtype mediating many of these responses (O2xe2x88x92 and LTB4/HNE release and cell adhesion) is established as A2a. The A2 subtype (A2a or A2b) mediating the other effects remains to be established.
Selective agonist activity at the A2a receptor is considered to offer greater therapeutic benefit than non-selective adenosine receptor agonists because interaction with other receptor subtypes is associated with detrimental effects in the lung in animal models and human tissue studies. For example, asthmatics, but not non-asthmatics, bronchoconstrict when challenged with inhaled adenosine. This response is at least in part due to the activation of the A1 receptor subtype. Activation of A1 receptors also promotes neutrophil chemotaxis and adherence to endothelial cells, thus promoting lung injury. Furthermore, many patients with a respiratory disease will be co-prescribed xcex22-agonists, and negative interaction has been shown in animal studies between isoprenaline and adenosine receptors negatively coupled to adenylate cyclase. Degranulation of human mast cells is promoted by activation of adenosine A2b receptors, thus selectivity over this receptor is also advantageous.
We have now surprisingly found the present purine derivatives inhibit neutrophil function and are selective agonists of the adenosine A2a receptor.
The present compounds may be used to treat any disease for which an adenosine A2a receptor agonist is indicated. They can be used to treat a disease where leukocyte (e.g. neutrophil, eosinophil, basophil, lymphocyte, macrophage)xe2x80x94induced tissue damage is implicated. They are useful as anti-inflammatory agents in the treatment of diseases of the respiratory tract such as adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis. The present compounds may also be used in the treatment of septic shock, male erectile dysfunction, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease, Heliobacter pylori-gastritis, non-Heliobacter pylon gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastro-intestinal tract or a psychotic disorder, or for wound healing.
Accordingly, in one aspect the present invention provides a compound of the formula: 
or a pharmaceutically acceptable salt or solvate thereof,
wherein R1 is hydrogen, C1-C6 alkyl or C3-C7 cycloalkyl, each optionally substituted by 1 or 2 substituents each independently selected from hydroxyl, fluorenyl, phenyl and naphthyl, said phenyl and naphthyl being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halo or cyano;
A is a bond or C1-C6 alkylene;
R2 is (i) hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl or naphthyl, said C3-C7 cycloalkyl, phenyl and naphthyl being optionally substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, amino-(C1-C6)-alkyl, fluoro-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, C2-C5 alkanoyl, halo, xe2x80x94OR3, cyano, xe2x80x94COOR3, C3-C7 cycloalkyl, xe2x80x94S(O)mR4, xe2x80x94NR3R3, xe2x80x94SO2NR3R3, xe2x80x94CONR3R3, xe2x80x94NR3COR4 or xe2x80x94NR3SO2R4, with the proviso that R2 is not hydrogen when A is a bond, or (ii) when A is C2-C6 alkylene, xe2x80x94NR3R3, xe2x80x94OR3, xe2x80x94COOR3, xe2x80x94OCOR4, xe2x80x94SO2R4, xe2x80x94CN, xe2x80x94SO2NR3R3, xe2x80x94NR3SO2R4, xe2x80x94NR3COR4 or xe2x80x94CONR3R3, or (iii) a C-linked, 4 to 11 membered, mono or bicyclic heterocycle having either from 1 to 4 ring nitrogen atom(s) or 1 or 2 nitrogen and 1 oxygen or 1 sulphur ring atoms, optionally C-substituted by oxo, C1-C6 alkoxy-(C1-C6)-alkyl, amino-(C1-C6)-alkyl, fluoro-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, fluoro-(C2-C5)-alkanoyl, halo, cyano, xe2x80x94OR5, R6, xe2x80x94COR5, xe2x80x94NR5R5, xe2x80x94COOR5, xe2x80x94S(O)mR6, xe2x80x94SO2NR5R5, xe2x80x94CONR5R5, xe2x80x94NR5SO2R6 or xe2x80x94NR5COR6 and optionally N-substituted by C1-C6 alkoxy-(C1-C6)-alkyl, amino-(C2-C6)-alkyl, fluoro-(C1-C6)-alkyl, fluoro-(C2-C5)-alkanoyl, R6, xe2x80x94COR5, xe2x80x94COOR6, xe2x80x94SO2R6, xe2x80x94SO2NR5R5 or xe2x80x94CONR5R5, or (iv) when A is C2-C6 alkylene, N-linked azetidinyl, pyrrolidinyl, morpholinyl, tetrahydroisoquinolinyl, piperidinyl or piperazinyl, each being optionally C-substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, amino-(C1-C6)-alkyl, fluoro-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, C2-C5 alkanoyl, halo, xe2x80x94OR3, cyano, xe2x80x94COOR3, C3-C7 cycloalkyl, xe2x80x94S(O)mR4, xe2x80x94NR3R3, xe2x80x94SO2NR3R3, xe2x80x94CONR3R3, xe2x80x94NR3COR4 or xe2x80x94NR3SO2R4 and said piperazinyl being optionally N-substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, amino-(C2-C6)-alkyl, fluoro-(C1-C6)-alkyl, C2-C5 alkanoyl, xe2x80x94COOR4, C3-C7 cycloalkyl, xe2x80x94SO2R4, xe2x80x94SO2NR3R3 or xe2x80x94CONR 3R3;
each R3 is independently selected from H, C1-C6 alkyl, phenyl or pyridinyl;
R4 is C1-C6 alkyl or phenyl;
R5 is H, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, naphthyl or het;
R6 is C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, naphthyl or het;
m is 0, 1 or 2;
R7 is hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, naphthyl, azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl or het, said azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl being optionally substituted by C1-C6 alkyl;
R8 is H or C1-C6 alkyl; and
xe2x80x9chetxe2x80x9d, used in the definitions of R5, R6 and R7, means C-linked pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl, each being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, cyano or halo.
Preferably, R1 is cyclohexyl or optionally substituted C1-C6 alkyl. More preferably, R1 is optionally substituted C1-C5 alkyl, and most preferably R1 is optionally substituted C1-C2 alkyl. Preferably, the C1-C6, C1-C5, or C1-C2 alkyl substitutents are selected from benzyl, fluorenyl, phenyl and hydroxyl. Preferably, when R1 is substituted by phenyl there are 1 or 2 phenyl group(s). Preferably, R1 is selected from 2,2-diphenylethyl, cyclohexyl,1-ethylpropyl, 1-benzyl-2-hydroxyethyl, 9H-fluoren-9-ylmethyl, and 1-benzyl-2-phenylethyl. Preferably, R1 is 2,2-diphenylethyl. Preferably, A is C1-C6 alkylene. Preferably, A is C1-C4 alkylene. Preferably, A is selected from methylene, 1,2-ethylene, 1,3-propylene, and 1,4-butylene. Preferably, A is 1,2-ethylene. Preferably, R2 is selected from phenyl, pyrrolidinyl, pyridinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted imidazolyl, morpholinyl, tetrahydroisoquinolyl, C1-C6 alkylamino, di- C1-C6 alkylamino, pyridinylamino, and xe2x80x94NR3SO2R4. Preferably, R2 is selected from phenyl, 2-pyridinyl, 1-piperazinyl, 4-piperidinyl, 1-pyrrolidinyl, 4-morpholinyl, 3,4-tetrahydro-2(1H)-isoquinolinyl, C1-C3 alkylamino, di- C1-C3 alkylamino, and substituted 1H-imidazol-4-yl.
Preferably, R2 is selected from isopropylamino, methylamino, dimethylamino, diethylamino, 1-methyl-1H-imidazol-4-yl, 5-methyl-1H-imidazol-4-yl, 4-methylpiperazin-1-yl, 1-(2-propyl)piperidin-4-yl and 2-pyridylamino. Preferably, R2 is piperidinyl optionally substituted by C1-C6 alkyl or methoxy. Preferably, R2 is piperidinyl optionally substituted in the 1-position or 4-position by C1-C6 alkyl or methoxy. Preferably, R2 is N-linked piperidinyl optionally C-substituted by C1-C6 alkyl or methoxy. Preferably, R2 is N-linked piperidinyl optionally C-substituted by C1-C3 alkyl or methoxy. Preferably, R2 is N-linked piperidinyl optionally C-substituted by methyl, methoxy or propyl. Preferably, R2 is N-linked piperidinyl optionally substituted in the 4-position by methyl, methoxy or propyl. Preferably, R2 is piperidin-1-yl, 4-(methyl)piperidin-1-yl, 4-(methoxy)piperidin-1-yl or 4-(prop-2-yl)piperidin-1-yl.
Preferably, R3 is methyl.
Preferably, R4 is methyl or phenyl.
Preferably, R7 is C1-C6alkyl.
Preferably, R7 is C1-C4 alkyl.
Preferably, R7 is ethyl or n-propyl.
Preferably, R8 is H.
In another aspect of the present invention, there is provided a compound of the formula (II), (III), (XI), (XIII), (XIV), (XV), (XVI), (XIX), (XIXb), (XIXc), or (XIXd): 
wherein R1 to R8, A, xe2x80x9chetxe2x80x9d , and m when present are as defined above; P1, P2, and P3 are protecting groups; and Z is a leaving group.
In another aspect of the present invention, there is provided a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, the process comprising the step of reacting an ester of formula (II): 
with an amine of the formula R2-A-NHR8 (X), wherein R1 to R8, A, xe2x80x9chetxe2x80x9d and m when present are as defined above.
In another aspect of the present invention, there is provided a process for the preparation of a compound of the formula (II): 
the process comprising the step of deprotecting a compound of formula (III): 
wherein P1 and P2 are protecting groups which may be the same or different or may be part of the same protecting group, and wherein R1 to R8, A, xe2x80x9chetxe2x80x9d, and in when present are as defined above.
In another aspect of the present invention, there is provided a process for the preparation of a compound of the formula (III): 
the process comprising the step of reacting a compound of the formula (XI): 
wherein P1 and P2 are protecting groups with trimethylsilyltrifluoromethanesulfonate and a compound of the formula (IV): 
wherein the compound of formula (IV) is derivatised with N,O-bis (trimethylsilyl) acetamide and then reacted with the compound of formula (XI), and wherein R1 to R8, A, xe2x80x9chetxe2x80x9d, and m when present are as defined above.
In another aspect of the present invention, there is provided a process for the preparation of a compound of formula (IV): 
by the alcoholysis and subsequent hydrolysis of a nitrile of formula (V): 
wherein R1 is R8, A, xe2x80x9chetxe2x80x9d, and m when present are as defined above.
In another aspect of the present invention, there is provided a process for the preparation of a compound of the formula (V): 
by the deprotection of a compound of formula (VI): 
wherein P3 is a protecting group, and R1 to R8, A xe2x80x9chetxe2x80x9d, and m when present are as defined above.
In another aspect of the present invention, there is provided a process for the preparation of a compound of the formula (VI): 
by substitution of the chloro group in a compound of the formula (VII): 
with a cyano group, wherein R1 is R8, A, xe2x80x9chetxe2x80x9d, and m when present are as defined above.
In another aspect of the present invention, there is provided a process for the preparation of a compound of the formula (VII): 
by reaction of a compound of formula (VIII): 
with an amino of formula R1NH2 (XII), wherein R1 to R8, A, xe2x80x9chetxe2x80x9d, and m when present are as defined above.
In another aspect of the present invention, there is provided a process for the preparation of the a compound of the formula (VIII): 
by the protection of 2,6-dichloro-9H-purine (IX): 
In the above definitions, halo means fluoro, chloro, bromo or iodo and alkyl, alkylene, alkanoyl and alkoxy groups containing the requisite number of carbon atoms can be unbranched or branched chain. The heterocycle as defined in R2, part (iii), above may be aromatic or fully or partially saturated. The expression xe2x80x98C-linkedxe2x80x99 used in the definitions of R2 and het means that the group is linked to the adjacent atom by a ring carbon. The expression xe2x80x98N-linkedxe2x80x99 used in the definitions of R2 means that the group is linked to the adjacent atom by a ring nitrogen. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. Examples of alkylene include methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene and 1,2-propylene. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and palmoate salts.
Suitable base salts are formed from bases which form non-toxic salts and examples are the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts.
For a review on suitable salts see Berge et al, J. Pharm. Sci., 1977, 66, 1-19.
The pharmaceutically acceptable solvates of the compounds of the formula (I) include the hydrates thereof.
Also included within the present scope of the compounds of the formula (I) are polymorphs thereof.
A compound of the formula (I) may contain one or more additional asymmetric carbon atoms and therefore exist in two or more stereoisomeric forms. The present invention includes the individual stereoisomers of the compounds of the formula (I) together with mixtures thereof together, where appropriate, with the individual tautomers of the compounds of the formula (I) and mixtures thereof.
Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
All the compounds of the formula (I) can be prepared by conventional routes such as by the procedures described in the general methods presented below or by the specific methods described in the Examples section, or by similar methods thereto. The present invention also encompasses any one or more of these processes for preparing the compounds of formula (I), in addition to any novel intermediates used therein. In the general methods described, R1, R2, R7, R8 and A are as previously defined for a compound of the formula (I) unless otherwise stated.
All the compounds of the formula (I) can be prepared according to the route shown in Scheme 1, wherein R9 is C1-C4 alkyl, preferably methyl or ethyl, and P1, P2 and P3 represent protecting groups. 
In Scheme 1, the compounds of the formula (I) may be prepared by reaction of an ester of the formula (II) with an amine of the formula
R2-A-NHR8xe2x80x83xe2x80x83(X). 
The reaction may be carried out at an elevated temperature, preferably from 100 to 150xc2x0 C. and optionally in the presence of a suitable solvent such as ethanol. In a typical procedure, the compound of the formula (II) and the amine of the formula (X) are heated together at about 120xc2x0 C. Compounds of formula (II) may be prepared by deprotection of a compound of the formula (III) wherein protecting groups P1 and P2 may be the same or different and may optionally form part of the same protecting group. Examples of suitable protecting groups will be apparent to the skilled person [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. Preferred individual protecting groups are alkanoyl and aroyl. Preferred protecting groups where P1 and P2 form part of the same protecting group are where P1 and P2 taken together are C1-C6 alkylene. Particularly preferred individual protecting groups are acetyl and benzoyl. A particularly preferred protecting group where P1 and P2 form part of the same protecting group is when P1 and P2 taken together are dimethylmethylene. Suitable conditions for the deprotection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P1 and P2 are each benzoyl, the protecting groups may be removed by treating a solution of the compound of the formula (III) in a suitable solvent, such as methanol, with a base such as potassium carbonate, typically at room temperature. Compounds of the formula (III) may be prepared by reaction of a compound of the formula (XI): 
(in which P1 and P2 are as defined above) with trimethylsilyl trifluoromethanesulfonate and a compound of the formula (IV) which has been derivatised with N,O-bis(trimethylsilyl)acetamide. In a typical procedure, the compound of the formula (IV) is heated in the presence of a suitable solvent, such as 1,1,1-trichloroethane, and N,O-bis(trimethylsilyl)acetamide at an elevated temperature, preferably under reflux. The mixture is then allowed to cool and the solvent is removed. The residue is treated with a solution of the compound of the formula (XI) in a suitable solvent such as toluene, followed by trimethylsilyl trifluoromethanesulfonate and the mixture is heated under a nitrogen atmosphere at a temperature between room temperature and the reflux temperature of the chosen solvent to give the compound of the formula (III). In the case of toluene, for example, a temperature of 110xc2x0 C. is preferred. Compounds of the formula (IV) may be prepared by a sequence of alcoholysis and hydrolysis applied to a nitrile of the formula (V). In a typical procedure, a solution of the nitrile of the formula (V) in an alcoholic solvent R9OH is treated a sodium alkoxide of the formula R9ONa and heated under reflux (R9 is as defined above). The resulting mixture is cooled, evaporated, dissolved in a suitable solvent such as tetrahydrofuran and treated with an acid such as hydrochloric acid, preferably 2N hydrochloric acid, to give a compound of the formula (IV). Compounds of the formula (V) may be prepared by deprotection of a compound of the formula (VI) wherein P3 is a suitable protecting group. Examples of suitable protecting groups will be apparent to the skilled person [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. A preferred protecting group is that in which P3 represents tetrahydropyran-2-yl. Suitable conditions for the deprotection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P3 is tetrahydropyran-2-yl, the protecting group may be removed by treating a solution of the compound of the formula (VI) in a suitable solvent, such as ethanol, with an acid such as hydrochloric acid. Compounds of formula (VI) may be prepared by substitution of the chloro group in a compound of the formula (VII) with a cyano group. In a typical procedure, a solution of the compound of the formula (VII) in a suitable solvent such as N,N-dimethylformamide is treated with zinc cyanide, tetrakis(triphenylphosphine)-palladium(0) and an acid acceptor such as triethylamine and heated under an atmosphere of nitrogen to between 80 and 120xc2x0 C., preferably to 100xc2x0 C. The product of the reaction is usually contaminated with an amount of the corresponding compound of the formula (V) which may be separated by routine chromatography. Compounds of the formula (VII) may be prepared by reaction of a compound of the formula (VIII) with an amine of the formula
R1NH2xe2x80x83xe2x80x83(XII). 
In a typical procedure, a solution of the compound of the formula (VIII) in a suitable solvent such as isopropyl alcohol is treated with the compound of the formula (XII) and heated at reflux, optionally in the presence of an acid acceptor such as N-ethyl-N-isopropyl-2-propylamine. Compounds of the formula (VIII) may be prepared by protection of 2,6-dichloro-9H-purine (IX). Examples of suitable protecting groups P3 will be apparent to the skilled person [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. A preferred protecting group is that in which P3 represents tetrahydropyran-2-yl. Suitable conditions for the protection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P3 is tetrahydropyran-2-yl, a solution of 2,6-dichloro-9H-purine (IX) and an acid catalyst such as 4-toluenesulphonic acid monohydrate in a suitable solvent such as ethyl acetate is heated to between 30 and 70xc2x0 C., preferably to 50xc2x0 C., and treated with a solution of 2,3-dihydropyran in a suitable solvent such as ethyl acetate.
All the compounds of the formula (I) can also be prepared according to the route shown in Scheme 2, wherein R9, P1, P2 and P3 are as defined above. 
In Scheme 2, the compounds of formula (I) may be prepared by deprotection of a compound of the formula (XIII). Suitable conditions for the deprotection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P1 and P2 are each benzoyl, the protecting groups may be removed by treating a solution of the compound of the formula (XIII) in a suitable solvent, such as methanol, with a base such as potassium carbonate, typically at room temperature. Compounds of the formula (XIII) may be prepared by reaction of a compound of the formula (XI): 
(in which P1 and P2 are as defined above) with trimethylsilyl trifluoromethanesulfonate and a compound of the formula (XIV) which has been derivatised with N,O-bis(trimethylsilyl)acetamide. In a typical procedure, the compound of the formula (XIV) is heated in the presence of a suitable solvent, such as 1,1,1-trichloroethane, and N,O-bis(trimethylsilyl)acetamide at an elevated temperature, preferably at reflux. The mixture is then allowed to cool and the solvent is removed. The residue is treated with a solution of the compound of the formula (XI) in a suitable solvent such as toluene followed by trimethylsilyl trifluoromethanesulfonate and the mixture is heated under a nitrogen atmosphere at a temperature between room temperature and the reflux temperature of the chosen solvent to give the compound of the formula (XIII). In the case of toluene, for example, a temperature of 90xc2x0 C. is preferred. Compounds of the formula (XIV) may be prepared by deprotection of a compound of the formula (XV). Suitable conditions for the deprotection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P3 is tetrahydropyran-2-yl, the protecting group may be removed by treating a solution of the compound of the formula (XV) in a suitable solvent, such as ethanol, with an acid such as hydrochloric acid. Compounds of the formula (XV) may be prepared by reaction of an ester of the formula (XVI) with an amine of the formula (X):
R2xe2x80x94Axe2x80x94NHR8xe2x80x83xe2x80x83(X) 
at an elevated temperature, preferably at 100 to 150xc2x0 C. In a typical procedure, the compound of the formula (XVI) and the amine of the formula (X) are heated together at 130xc2x0 C. Compounds of the formula (XVI) may be prepared by a sequence of alcoholysis and hydrolysis performed on a nitrile of the formula (VI). In a typical procedure, a solution of the nitrile of the formula (VI) in an alcoholic solvent R9OH is treated with the sodium alkoxide of the formula R9ONa and heated under reflux. The resulting mixture is cooled, evaporated, dissolved in a suitable solvent such as a mixture of tetrahydrofuran and water (preferably 3:1 by volume) and treated with an acid such as acetic acid. The resulting mixture is heated at an elevated temperature, preferably under reflux, to give the compound of the formula (XVI).
Compounds of the formula (XI), as used in Schemes 1 and 2, may be prepared as shown in Scheme 3, wherein P1 and P2 are as defined above. 
Compounds of the formula (XI) may be prepared by treatment of a compound of the formula (XVII) with a mixture of acetic acid, acetic anhydride and a strong acid such as hydrochloric or sulphuric acid with cooling (typically to xe2x88x9210xc2x0 C.). A compound of formula (XVII) may be prepared from an acid of the formula (XVIII) by activation of the acid as, for example, an acid chloride and treatment of this activated intermediate with an amine of the formula (XIXa):
R7NH2xe2x80x83xe2x80x83(XIXa). 
In a typical procedure, a compound of formula (XVIII) is dissolved in a suitable inert solvent (e.g. dichloromethane) and treated with oxalyl chloride and a catalytic amount of N,N-dimethylformamide. After removal of excess solvent and reagent by evaporation under reduced pressure, the residue is dissolved in anhydrous dichloromethane and treated with an amine of the formula (XIXa). With regard to the conditions employed in later steps, it may be appropriate to change the protecting groups P1 and P2 in compounds of formula (XVII). Alternative, suitable protecting groups are well-known to the skilled person [e.g. xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical case, a solution of the compound of formula (XVII) wherein P1 and P2 taken together are dimethylmethylene in a suitable solvent such as methanol may treated with an acid such as pyridinium para-toluenesulphonate to give a compound of formula (XVII) wherein P1 and P2 are both replaced by H which may be subsequently reprotected with other functionality. For instance, the compound of formula (XVII) wherein P1 and P2 are both replaced by H may be dissolved in a suitable solvent such as dichloromethane and the resulting solution may be treated with an acid acceptor, such as pyridine, and benzoyl chloride to give a compound of formula (XVII) wherein P1 and P2 are each benzoyl. Compounds of formula (XVIII) are known in the art, for example in J. Amer. Chem. Soc., 1958, 80, 5168 where P1 and P2 taken together are dimethylmethylene.
Amines of the formulae R7NH2 (XIXa), R1NH2 (XII) and R2xe2x80x94Axe2x80x94NHR8 (X) are either commercially available or may be prepared by standard techniques well known to persons skilled in the art.
All the compounds of the formula (I) may alternatively be prepared by condensation of an acid of the formula (XIX) with an amine of the formula (X) as shown in Scheme 4. 
The condensation is typically carried out under conventional peptide-coupling conditions. For example, a solution of the acid (XIX) in a suitable solvent such as dichloromethane may be treated firstly with a suitable coupling agent such as carbonyl diimidazole and subsequently with a compound of the formula (X). An acid of the formula (XIX) may be prepared by hydrolysis of a compound of the formula (II). In order to carry out the hydrolysis, a compound of the formula (II) is typically dissolved in a suitable solvent such as ethanol and treated with a suitable base such as aqueous sodium hydroxide.
Compounds of the formula (I) may alternatively be prepared by an aminocarbonylation reaction of a compound of the formula (XIXb): 
wherein Z is a suitable leaving group such as bromo, iodo, Sn(C1-C12 alkyl)3 or CF3SO2Oxe2x80x94, preferably iodo, with a compound of formula R2xe2x80x94Axe2x80x94NHR8 (X) in the presence of carbon monoxide and a suitable coupling catalyst. Preferably, the catalyst is a palladium (II) catalyst, more preferably 1,1xe2x80x2- bis(diphenylphosphino)ferrocenedichloropalladium (II) (optionally as a 1:1 complex with dichloromethane). Alternatively, palladium (II) acetate may be used in the presence of a suitable ligand such as 1,1xe2x80x2- bis(diphenylphosphino)ferrcene, triphenlyphospine, tri(o-tolyl)phosphine or (R)xe2x80x94, (S)xe2x80x94 or racemic 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl.
In a typical procedure the reaction is carried out in a sealed vessel in the presence of carbon monoxide at an elevated pressure, e.g. about 345 kPa (50 psi), at an elevated temperature, e.g. about 60xc2x0 C., and in a suitable solvent, e.g. tetrahydrofuran, methanol or ethanol. Optionally, a suitable organic base may be present such as tertiary amine, e.g. triethylamine, N-ethyldiisopropylamine or 4-methylmorpholine.
The intermediates of the formula (XIXc) can be prepared as shown in Scheme 5. 
wherein Z is as previously defined for the compound of the formula (XIXb) and Ac is acetyl.
In a typical procedure a compound of the formula (XIXd) is reacted with an amine of the formula R1NH2 (XII) in the presence of a suitable acid acceptor, e.g. triethylamine, and in a suitable solvent, e.g. acetonitrile, at an elevated temperature, if necessary. The product of the formula (XIXc) obtained can be deprotected by hydrolysis to provide a compound of the formula (XIXb) by a conventional procedure such as by using a suitable inorganic base, e.g. sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or caesium carbonate, and in a suitable solvent, e.g. methanol, ethanol, isopropanol, 1,2-dimethoxyethane, tetrahydrofuran, dimethylformamide, acetone, 2-butanone or 4-methyl-2-pentanone, optionally under aqueous conditions, at from 0xc2x0 C. to the reflux temperature of the solvent, e.g. room temperature. Alternatively, the deprotection can be carried out using a suitable amine base such as triethylamine, diisopropylethylamine, 4-methylmorpholine, ammonia, methylamine, ethylamine or dimethylamine in a suitable solvent such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran or dicholromethane at from 0xc2x0 C. to the reflux temperature of the solvent. Compounds of the formula (XIXd) can be prepared by a conventional procedure.
A pharmaceutically acceptable salt of a compound of the formula (I) may be readily prepared by mixing together solutions of a compound of the formula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
The anti-inflammatory properties of the compounds of the formula (I) are demonstrated by their ability to inhibit neutrophil function which indicates A2a receptor agonist activity. This is evaluated by determining the compound profile in an assay where superoxide production was measured from neutrophils activated by fMLP. Neutrophils were isolated from human peripheral blood using dextran sedimentation followed by centrifugation through Ficoll-Hypaque solution. Any contaminating erythrocytes in the granulocyte pellet were removed by lysis with ice-cold distilled water. Superoxide production from the neutrophils was induced by fMLP in the presence of a priming concentration of cytochalasin B. Adenosine deaminase was included in the assay to remove any endogenously produced adenosine that might suppress superoxide production. The effect of the compound on the fMLP-induced response was monitored colorometrically from the reduction of cytochrome C within the assay buffer. The potency of the compounds was assessed by the concentration giving 50% inhibition (IC50) compared to the control response to fMLP.
In this assay, the compounds of the invention have IC50 values of less than 200 n M. The compounds of Examples 7, 10, 12, 16, 20, 21, 27 and 31 are most effective and have IC50 values of less than 40 n M.
The present invention thus also provides a pharmaceutical composition including a compound of the formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient, diluent or carrier.
The present invention also provides a compound of the formula (I) as defined above, or a pharmaceutically acceptable salt, solvate or composition thereof, for use as a medicament.
The present invention also provides a compound of the formula (I) as defined above, or a pharmaceutically acceptable salt, solvate or composition thereof, for use as a medicament to treat a disease for which a A2a receptor agonist is indicated.
The present invention also provides the use of a compound of the formula (I) as defined above, or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament to treat a disease for which a A2a receptor agonist is indicated.
The present invention also provides a compound of the formula (I) as defined above, or a pharmaceutically acceptable salt, solvate or composition thereof, for use as an anti-inflammatory agent.
The present invention also provides the use of a compound of the formula (I) as defined above, or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of an anti-inflammatory agent.
The present invention also provides the use of a compound of the formula (I) as defined above, or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the treatment of a respiratory disease. The present invention also provides the use as referred to above where the disease is selected from the group consisting of adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema bronchiectasis, chronic sinusitis and rhinitis.
The present invention also provides the use of a compound of the formula (I) as defined above, or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the treatment of septic shock, male erectile dysfunction, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease, Heliobacter pylori-gastritis, non-Heliobacter pylori gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastro-intestinal tract or a psychotic disorder, or for wound healing.
The present invention also provides a method of treatment of a mammal, including a human being, to treat a disease for which a A2a receptor agonist is indicated including treating said mammal with an effective amount of a compound of the formula (I) as defined above or with a pharmaceutically acceptable salt, solvate or composition thereof.
The present invention also provides a method of treatment of a mammal, including a human being, to treat an inflammatory disease including treating said mammal with an effective amount of a compound of the formula (I) as defined above or with a pharmaceutically acceptable salt, solvate or composition thereof.
The present invention also provides a method of treatment of a mammal, including a human being, to treat a respiratory disease including treating said mammal with an effective amount of a compound of the formula (I) as defined above or with a pharmaceutically acceptable salt, solvate or composition thereof. The present invention also provides the method as referred to above, wherein the disease is selected from the group consisting of adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis.
The present invention also provides a method of treatment of a mammal, including a human being, to treat septic shock, male erectile dysfunction, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease, Heliobacter pylori-gastritis, non-Heliobacter pylori gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastro-intestinal tract or a psychotic disorder, or for wound healing, including treating said mammal with an effective amount of a compound of the formula (I) as defined above or with a pharmaceutically acceptable salt, solvate or composition thereof.
The compounds of the formula (I) can be administered alone but will generally be administered in admixture with a suitable pharmaceutically acceptable excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
For example, the compounds of the formula (I) can be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, sustained-, pulsed- or controlled-release applications.
Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or a high molecular weight polyethylene glycol. For aqueous suspensions and/or elixirs, the compounds of the formula (I) may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol or glycerin, and combinations thereof.
The compounds of the formula (I) can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques. They are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
For oral and parenteral administration to human patients, the daily dosage level of the compounds of the formula (I) will usually be from 0.01 to 100 mg/kg, body weight of the subject to be treated, preferably from 0.1 to 100 mg/kg (in single or divided doses).
Thus tablets or capsules of the compound of the formula (I) may contain from 5 to 500 mg of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
The compounds of formula (I) can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomiser or nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray, atomiser or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the formula (I) and a suitable powder base such as lactose or starch.
Aerosol or dry powder formulations are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d contains from 20 to 4000 xcexcg of a compound of the formula (I) for delivery to the patient. The overall daily dose with an aerosol will be in the range of from 20 xcexcg to 20 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
Alternatively, the compounds of the formula (I) can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment, gel, suspension, dusting powder, spray or drug-incorporated dressing (e.g. a tulle dressing, a white soft paraffin or polyethylene glycol impregnated gauze dressing, or hydrogel, hydrocolloid, alginate or film dressing). The compounds of the formula (I) may also be transdermally administered, for example, by the use of a skin patch.
For application topically to the skin, the compounds of the formula (I) can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. They can also be formulated as a hydrogel with cellulose or polyacrylate derivatives or other viscosity modifiers.
It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment.